Macrolactin compounds are macrolide antibiotics having a 24-membered lactone ring (J. Am. Chem. Soc., 1989, 111, 7519-7524). It has been reported that the compounds are produced from unclassified ocean bacteria, actinomyces and Bacillus strains, and 21 macrolactin compounds have been identified. These macrolactin compounds have a variety of pharmacological activities. Prior studies on the pharmacological activities of the macrolactin compounds are as follows.
William Fenical disclosed anti-viral activity of MA against Herpes simplex and HIV in 1989. Ick-Dong Yoo obtained MA from Actinomadura sp. strain in 1997 and studied protection of neurocytes derived from glutamate using the MA. In 2001, Hiroshi Sano isolated MA from Bacillus sp. PP19-H3 strain and studied the anti-bacterial activity of MA against Staphylococcus aureus IFO 12732 and Bacillus subtilis IFO 3134 strains. Sung-Won Choi obtained MA from Streptomyces sp. YB-401 strain in 2003 and disclosed the inhibition effect of MA on biosynthesis of cholesterol. In 2004, Keun-Hyung Park separated MA from Bacillus amyloliquefaciens CHO104 strain and studied anti-bacterial activity of MA against Staphylococcus aureus KCTC 1928, Escherichia coli KCTC 2593 and Botrytis cinerea. Joo-Won Suh obtained MA from Bacillus sp. Sunhua strain in 2005 and studied inhibition of the Streptomyces scabies inducing potato common scab using the MA. In 2006, Gabriella Molinari isolated MA, MMA and SMA from Bacillus subtilis DSM 16696 strain and studied anti-bacterial activity of each compound against vancomycin-resistant Enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA) and Burkholderia cepacia. In this study, it was reported that each of MMA and SMA had superior anti-bacterial activity against the test bacteria, while MA showed anti-bacterial effect against MRSA only.
Even though macrolactin compounds are known to have various pharmacological activities, studies about the anti-inflammatory effect of macrolactin compounds have never been reported until now.
Inflammation is a defensive response to an injury which has occurred in an affected part of a living system. That is, an inflammatory response is a defensive response for restoring the original condition by responding to a harmful stimulus and removing the injury caused by the stimulus.
Nitric oxide (hereinafter, “NO”), one of the substances that induce inflammation, is produced in endothelial cells or macrophages in a normal state. NO, a mediator participating in vasodilation, platelet adhesion and aggregation, neurotransmission, movement of the digestive system, and erection, etc., is produced in inflammatory cells and non-immune cells, and also performs a defensive action against microorganism infection. Stimulation due to lipopolysaccharide (hereinafter, “LPS”), inflammation-inducing factors and irradiation, etc. induces the expression of intracellular iNOS protein and produces NO continuously to induce inflammatory disease.
Another inflammation-inducing substance, prostaglandin E2 (hereinafter, “PGE2”) is a kind of hormone derived from arachidonic acid and participates in various physiological activities. PGE2 is produced by the expression of COX-2 protein. Drugs that suppress the expression of COX-2 have analgesic, antiedemic, antipyretic, anti-inflammatory and anticoagulant effects, etc. by the inhibition of PGE2 production in inflammatory foci, and therefore they can be used for prevention and treatment of thrombus, edema, infarction, stroke and cerebrovascular diseases.
The above two inflammation-inducing substances, iNOS and COX-2, are closely related to each other. For example, excessively produced NO may affect the expression of COX-2. Accordingly, an inhibitor of the activity of iNOS and COX-2 is considered to have high potential for development as a drug for preventing and treating various diseases (e.g., inflammatory diseases) caused by excessive production of NO and PGE2 metabolites.
Until now, steroids and non-steroidal anti-inflammatory drugs (NSAIDs) have been used appropriately for the treatment of acute and chronic inflammatory diseases. However, conventional anti-inflammatory agents have considerable adverse effects, especially when used over a long time. Thus, it is highly required to develop a novel inflammatory agent with few side effects.